A fatal drug interaction between clozapine and fluoxetine

A case is presented of a fatal drug interaction caused by ingestion of clozapine (Clozaril) and fluoxetine (Prozac). Clozapine is a tricyclic dibenzodiazepine derivative used as an "atypical antipsychotic" in the treatment of severe paranoid schizophrenia. Fluoxetine is a selective serotonin reuptake inhibitor used for the treatment of major depression. Clinical studies have proven that concomitant administration of fluoxetine and clozapine produces increased plasma concentrations of clozapine and enhances clozapine's pharmacological effects due to suspected inhibition of clozapine metabolism by fluoxetine. Blood, gastric, and urine specimens were analyzed for fluoxetine by gas chromatography/mass spectrometry (GC/MS) and for clozapine by gas-liquid chromatography (GLC). Clozapine concentrations were: plasma, 4.9 micrograms/mL; gastric contents, 265 mg; and urine, 51.5 micrograms/mL. Fluoxetine concentrations were: blood, 0.7 microgram/mL; gastric contents, 3.7 mg; and urine 1.6 micrograms/mL. Norfluoxetine concentrations were: blood, 0.6 microgram/mL, and none detected in the gastric contents or urine. Analysis of the biological specimens for other drugs revealed the presence of ethanol (blood, 35 mg/dL; vitreous, 56 mg/dL; and urine 153 mg/dL) and caffeine (present in all specimens). The combination of these drugs produced lethal concentrations of clozapine and high therapeutic to toxic concentrations of fluoxetine. The deceased had pulmonary edema, visceral vascular congestion, paralytic ileus, gastroenteritis and eosinophilia. These conditions are associated with clozapine toxicity. The combined central nervous system, respiratory and cardiovascular depression of these drugs was sufficient to cause death. The death was determined to be a clozapine overdose due to a fatal drug interaction.     

Ocean inherent optical property estimation from irradiances

A method is evaluated for estimating the absorption coefficient a and the backscattering coefficient b(b) from measurements of the upward and downward irradiances E(u)(z) and E(d)(z). With this method, the reflectance ratio R(z) and the downward diffuse attenuation coefficient K(d)(z) obtained from E(u)(z) and E(d)(z) are used to estimate the inherent optical properties R(infinity) and K(infinity) that are the asymptotic values of R(z) and K(d)(z), respectively. For an assumed scattering phase function beta , there are unique correlations between the values of R(infinity) and K(infinity) and those of a and b(b) that can be derived from the radiative transfer equation. Good estimates of a and the Gordon parameter G = b(b)/(a + b(b)) can be obtained from R(infinity) and K(infinity) if the true scattering phase function is not greatly different from the assumed function. The method works best in deep, homogeneous waters, but can be applied to some cases of stratified waters. To improve performance in shallow waters where bottom effects are important, the deep- and shallow-measurement reflectance models also are developed.     

Transgenic mice expressing human ApoB95 and ApoB97. Evidence that sequences within the carboxyl-terminal portion of human apoB100 are important for the assembly of lipoprotein

The structural features of apolipoprotein (apo) B that are important for its covalent linkage to apo(a) to form lipoprotein(a) (Lp(a)) are incompletely understood. Although apoB100 cysteine 4326 is required for the disulfide linkage with apo(a), other structural features, aside from a single free cysteine residue, must be important for apoB's initial interaction with apo(a) and for facilitating the formation of the disulfide bond. To determine if sequences carboxyl-terminal to cysteine 4326 affect the efficiency of Lp(a) formation, we used "pop-in, pop-out" gene targeting in a human apoB yeast artificial chromosome to introduce nonsense mutations into exon 29 of the apoB gene. The mutant yeast artificial chromosomes, which coded for the truncated versions of human apoB, apoB95, and apoB97, were then used to express these mutant forms of apoB in transgenic mice. As judged by in vitro assays of Lp(a) formation, apoB95 (4330 amino acids) formed a small amount of Lp(a) but did so slowly. In contrast, apoB97 (4397 amino acids) formed Lp(a) rapidly, although not quite as rapidly as the full-length apoB100 (4536 amino acids). These results were supported by an analysis of double-transgenic mice expressing both human apo(a) and either apoB95 or apoB97. In mice expressing both apoB95 and apo(a), there was only a trace amount of Lp(a) in the plasma, and most of the apo(a) was free, whereas in mice expressing both apoB97 and apo(a), virtually all of the apo(a) was bound to apoB97 in the form of Lp(a). These results show that sequences carboxyl-terminal to apoB95 (amino acids 4331-4536) are not absolutely required for Lp(a) formation, but this segment of the apoB molecule, particularly residues 4331-4397, is necessary for the efficient assembly of Lp(a).     

A Lagrangian Scheme for the Solution of Nonlinear Diffusion Equations Using Moving Simplex Meshes

A Lagrangian numerical scheme for solving nonlinear degenerate Fokker–Planck equations in space dimensions \(d\ge 2\) is presented. It applies to a large class of nonlinear diffusion equations, whose dynamics are driven by internal energies and given external potentials, e.g. the porous medium equation and the fast diffusion equation. The key ingredient in our approach is the gradient flow structure of the dynamics. For discretization of the Lagrangian map, we use a finite subspace of linear maps in space and a variational form of the implicit Euler method in time. Thanks to that time discretisation, the fully discrete solution inherits energy estimates from the original gradient flow, and these lead to weak compactness of the trajectories in the continuous limit. Consistency is analyzed in the planar situation, \(d=2\). A variety of numerical experiments for the porous medium equation indicates that the scheme is well-adapted to track the growth of the solution’s support.     

Negative normal stress in semiflexible biopolymer gels

When subject to stress or external loads, most materials resist deformation. Any stable material, for instance, resists compression-even liquids. Solids also resist simple shear deformations that conserve volume. Under shear, however, most materials also have a tendency to expand in the direction perpendicular to the applied shear stress, a response that is known as positive normal stress. For example, wet sand tends to dilate when sheared, and therefore dries around our feet when we walk on the beach. In the case of simple solids, elastic rods or wires tend to elongate when subject to torsion. Here, we show that networks of semiflexible biopolymers such as those that make up both the cytoskeleton of cells and the extracellular matrix exhibit the opposite tendency: when sheared between two plates, they tend to pull the plates together. We show that these negative normal stresses can be as large as the shear stress and that this property is directly related to the nonlinear strain-stiffening behaviour of biopolymer gels.     

A frequent activated smoothened mutation in sporadic basal cell carcinomas

Basal-cell carcinomas (BCCs) are the most common cancer in Caucasians. It has been reported that the patched gene is inactivated in 30-40% sporadic BCCs and 20% sporadic medulloblastomas via loss of heterozygosity and nonsense mutations. Recently, two activating smoothened mutations have been found in the sporadic basal cell carcinomas. One, at base pair 1604 (G-to-T transversion) of exon 9, changes codon 535 from tryptophan to leucine, and the other, at base pair 1685 (G-to-A transition) of exon 10, changes codon 562 from arginine to glutamine (Xie et al., 1998). In our study, 1604G-->T was found in 20 out of 97 (20.6%) sporadic BCCs. The high prevalence indicates that 1604G is the mutation hot spot in our tumor samples. This mutation was detected in all three histological subtypes of BCCs, suggesting that smoothened mutation is an early event during the development of the tumor. Our finding of a high smoothened mutation rate, together with high frequent patched gene mutations reported recently, indicates that activation of the hedgehog signal transduction pathway is the most common and early event in the development of sporadic BCCs. Additionally, to determine whether smoothened, like patched, is also involved in the carcinogenesis of medulloblastomas, we screened medulloblastoma samples for these two mutations by restriction analysis. We have found the 1604G-->T mutation in 1 out of 21 medulloblastomas. This result confirmed smoothened gene involvement in the carcinogenesis of medulloblastoma.     

The effects of processing variables on stress development in ultraviolet-cured coatings

A cantilever deflection technique was used to monitor stress development during ultraviolet photo-cure of acrylate coatings to the glassy state. Two coating systems were studied: a trifunctional monomer (trimethylol propane triacrylate, TMPTA) and a tetrafunctional monomer (pentaerythritol tetraacrylate, PETA). Both were photoinitiated with 2,2-dimethoxy-2-phenylacetophenone (DMPA). Average in-plane stresses of up to 30 MPa were measured upon curing at room temperature. The rate and magnitude of stress development rose with the photoinitiator concentration and with light intensity. Curing with more strongly absorbed light had similar effects. Light absorption caused decreased stress magnitudes in thicker coatings. Somewhat unexpectedly, the rate and magnitude of stress development increased with monomer functionality even though the conversion fell. Moreover, curing thick coatings with high radical concentrations (strongly absorbing light and large photoinitiator concentrations) caused ripple defects to form. With the appearance of these defects, stress ceased to rise with the photoinitiator concentration. Fourier transform infrared spectroscopy was employed to monitor conversion and to help understand these stress development trends. © 1997 John Wiley & Sons, Inc. J Appl Polym Sci 66: 1267–1277, 1997     

Amphipathic polymers with stimuli‐responsive microdomains for water remediation: Binding studies with p‐cresol

Amphipathic, stimuli‐responsive water‐soluble polymers have been investigated as potential remediation agents for micellar enhanced ultrafiltration (MEUF). The systems represent divergent architectural types, a triblock ABA copolymer of PEO‐PPO‐PEO, an n‐octylamide modified poly(sodium maleate‐alt‐ethyl vinyl ether), and the transport protein, bovine serum albumin. Each type exhibits stimuli‐dependent microphase separation or domain formation in response to temperature, pH, and/or ionic strength changes. Segmental associations result in hydrophobic clusters resembling those present in small molecule surfactant micelles. The effects of such segmental aggregation on sequestration of a model hydrophobic foulant, p‐cresol, have been investigated using equilibrium dialysis. The favorable molar binding values, the large hydrodynamic dimensions of the stable polymer aggregates, and potential reversibility of foulant loading could have commercial utility in high flow rate, multiple‐pass remediation processes. © 1999 John Wiley & Sons, Inc. J Appl Polym Sci 74: 2290–2300, 1999     

Analysis of nitro-polycyclic aromatic hydrocarbons in conventional diesel and Fischer-Tropsch diesel fuel emissions using electron monochromator-mass spectrometry

The presence of nitro-polycyclic aromatic hydrocarbons (NPAHs) in diesel fuel emissions has been studied for a number of years predominantly because of their contribution to the overall health and environmental risks associated with these emissions. Electron monochromator-mass spectrometry (EM-MS) is a highly selective and sensitive method for detection of NPAHs in complex matrixes, such as diesel emissions. Here, EM-MS was used to compare the levels of NPAHs in fuel emissions from conventional (petroleum) diesel, ultra-low sulfur/low-aromatic content diesel, Fischer-Tropsch synthetic diesel, and conventional diesel/synthetic diesel blend. The largest quantities of NPAHs were detected in the conventional diesel fuel emissions, while the ultra-low sulfur diesel and synthetic diesel fuel demonstrated a more than 50% reduction of NPAH quantities when compared to the conventional diesel fuel emissions. The emissions from the blend of conventional diesel with 30% synthetic diesel fuel also demonstrated a more than 30% reduction of the NPAH content when compared to the conventional diesel fuel emissions. In addition, a correlation was made between the aromatic content of the different fuel types and NPAH quantities and between the nitrogen oxides emissions from the different fuel types and NPAH quantities. The EM-MS system demonstrated high selectivity and sensitivity for detection of the NPAHs in the emissions with minimal sample cleanup required.